US4769453A - Bis-indolic compounds - Google Patents

Bis-indolic compounds Download PDF

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Publication number
US4769453A
US4769453A US06/275,050 US27505081A US4769453A US 4769453 A US4769453 A US 4769453A US 27505081 A US27505081 A US 27505081A US 4769453 A US4769453 A US 4769453A
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cooch
hydrogen
double bond
ethyl
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Pierre Potier
Nicole Langlois
Yves Langlois
Francoise Gueritte
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Centre National de la Recherche Scientifique CNRS
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Agence National de Valorisation de la Recherche ANVAR
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a process for the preparation of bis-indolic compounds and the bis-indolic compounds obtained by this process.
  • alkaloids such as vinblastine or vincristine which correspond to the formula ##STR1## and which can be isolated from a number of species of Catharanthus, in particular C. roseus and which have anti-tumoral properties.
  • these alkaloids are only present in very small quantities in the plant, thus it is of particular interest to be able to prepare semi-synthetic derivatives which have anti-tumoral properties and which can be easily obtained from more accessible products.
  • R' 1 represents a hydrogen atom or an alkoxy, acyl, formyl or haloacyl radical
  • R' 2 represents a hydrogen atom or a alkoyl radical
  • R' 3 and R" 3 identical or different, represent a hydrogen atom or a hydroxyl, alkenoyloxyl radical or,
  • R' 3 and R" 3 together form a carbonyl grouping
  • R' 3 and R' 5 together form an epoxy bridge or a double bond
  • R' 4 represents a hydrogen atom or an alkanoyloxy carbonyl, hydroxy methyl or alkanoyloxy methyl radical
  • R' 5 and R" 5 identical or different, represent a hydrogen atom or a a hydroxyl, alkanoyloxyl, ethyl or hydroxy-2 ethyl radical,
  • R' 6 represents a hydrogen atom or an ethyl, hydroxy-2 ethyl or acetyl radical
  • R 1 represents a hydrogen atom or an alkoyl formyl or acyl radical
  • R 2 represents a hydrogen atom or an alkoxy radical
  • R 3 represents a hydrogen atom or a hydroxyl or alkanoyloxyl radical or alternatively R 3 and R 4 together form an epoxy bridge or a double bond,
  • R 4 represents a hydrogen atom or a hydroxyl or alkanoyloxyl radical or alternatively R 4 and R 5 together form an epoxy bridge,
  • R 6 represents an alkanoyloxy carbonyl, hydrazidoacetamido, hydroxymethyl or alkanoyloxyl radical
  • R 5 and R 7 represent a hydrogen atom or a hydroxyl or alkanoyloxyl radical
  • alkoyl radicals mentioned in the present specification are preferably straight or branched lower alkoyl radicals having from 1 to 5 carbon atoms, such as methyl and ethyl radicals.
  • alkoxy radicals mentioned in the present specification are preferably lower alkoxy radicals corresponding to the preceeding alkoyl radicals, i.e. ethoxy and methoxy radicals.
  • acyl radicals mentioned in the present specification are for example acyl radicals arising from saturated or unsaturated lower carboxylic acids, such as acetyl and propionyl radicals.
  • alkanoyloxy radicals are preferably radicals corresponding to the preceeding acyl radicals, such as acetyloxy radical.
  • alkoyloxycarbonyl radicals are preferably radicals in which the alkoyl part corresponds to the above preferred definition, for example methoxycarbonyl radical.
  • non-toxic pharmaceutically acceptable salts be prepared such as the salts of inorganic acids such as hydrochloric acid, or of organic acids such as acetic acid.
  • the present invention relates to a process for the preparation of a compound of formula I, characterised in that a compound of the formula II ##STR3## is made to react with a compound of formula III ##STR4## in these formulae, the various substituents have the meaning given for formula I and n is the whole number 0 or 1,
  • Preferred immonium ion forming agents are the halides, anhydrides or salts of organic or inorganic acids in particular halogenated or unhalogenated (in particular fluorinated) carboxylic acids.
  • the salts of mercury (II) should be mentioned.
  • the immonium ion forming reagents are for example acetic acid anhydride or trifluoroacetic acid anhydride, or mercury acetate or trifluoro acetate, or mercury tetracetate ethylenediamine.
  • the immonium ion of formula IV is of course neutralised in the reaction mixture by the anion from the immonium ion forming reagent.
  • the immonium ion of the general formula IV is obtained by treating the mixture of the alkaloide of general formula II and of the alkaloide of general formula III, or of the Nb'-oxide of the latter, in solution in an organic solvent with an excess of the immonium ion forming reagent.
  • an organic solvent a chlorinated solvent such as methylene chloride, dichloroethane or chloroform is used.
  • the reduction of the immonium ion IV into a compound of the general formula I is preferably carried out by means of an alkaline borohydride such as sodium borohydride or by catalytic hydrogenation in the presence of a suitable catalyst.
  • the reduction is generally carried out in an organic solvent such as an alcohol and more particularly methanol or ethanol.
  • the reduction stage may be conducted in the reaction mixture originating from the first stage of the process or alternatively it is possible to evaporate the solvent of the first stage before carrying out the reduction in another solvent.
  • the process according to the present invention has the advantage over the previously known processes of permitting the preparation directly of the products of which the C 16 configuration is identical to that of natural products, the compounds having an unnatural C 16 configuration manifesting little or no anti-tumoral properties.
  • the process according to the invention can lead to a mixture of constituents of the general formula I having the natural or unnatural configuration (in 16) which can be isolated and purified by physical or chemical methods such as chromatography, gel-filtration or crystallisation.
  • the oxidising agent one can use perbenzoic acids such as p-nitroperbenzoic acid.
  • the compounds of formula II or III are known or can be prepared by known processes.
  • the present invention also relates to the new semi-synthetic alkaloides of formula I, in particular those having the natural configuration, for example the compounds of formula I which may be obtained by the process according to the present invention and more particularly the following alkaloides which will be designated by the nature of the alkaloides which constitute them:
  • Vindoline or desacetyl vindoline or dihydro-14,15-dihydrovindoline--catharanthine Vindoline or desacetyl vindoline or dihydro-14,15-dihydrovindoline--catharanthine.
  • the present invention also relates to the alkaloides of formula I obtained by the process according to the present invention.
  • the dry residue obtained was dissolved in 10 cm 3 of methanol and the solution obtained was cooled to 0° C. Then several times an excess of sodium borohydride was added. After 15 min at 0° C. the reaction mixture is dissolved by 100 cm 3 of water and the solution is extracted by 2 times 100 cm 2 and 2 times 50 cm 3 of chloroform. The organic phase was washed by 30 cm 3 of water and dried on anhydrous sodium sulphate. After filtration the solution was concentrated dry at reduced pressure (15 mm of mercury). The crude product obtained (492 mg) was separated into its constituents by chromatography on a thick layer of silica using the following clutriant systems:
  • Mass spectrum peaks at m/e: 792 (M + ⁇ ), 761, 733, 670, 633, 611, 525, 469, 336, 282, 135, 121.
  • Mass spectrum peaks at m/e: 792 (M + ⁇ ), 733, 670, 633, 610, 525, 469, 336, 282, 135, 121.
  • Mass spectra of I-3, I-4, I-5 peaks at m/e 794 (M + .), 763, 735, 635, 610, 469, 338, 282, 222, 188, 138 (base peak), 135, 124, 122, 121, 107.
  • I-7 [I-6 (16'R, 20'S)] or epi-16'I-6
  • I-8 [I-6 (16'R, 20'R)], or epi-20' I-7 12 mg
  • RMN (240 MHz): 8.83 (N a' --H); 7.2 to 6.9 aromatic protons; 6.56 (s 1H) and 5.91 (s 1H) C 9 --H and C 12 --H; 5.85 and 5.24 (2 m 2H) C 14 --H and C 15 --H; 5.19 (s 1H) C 17 --H; 3.83 (s 3H); 3.68 (s 1H), 3.66 (s 3H); C 16 --COOCH 3 ; C 16' --COOCH 3 and C 1 --OCH 3 ; 2.60 (s 3H) N a --CH 3 ; 2.04 (s 3H) C 17 --OCOCH 3 ; 0.9 (t 3H) and 0.63 (t 3H) C 18 --H and C 18' --H.
  • Mass spectrum M + at m/e 794, 762, 735, 663, 634, 468, 338, 282, 135, 124.
  • RMN (60 MHz): 7.8-7.4 (2H) C 16 --OH and N a --H; 7.4-6.90 (aromatic protons); 6.0 (s 1H) C 9 --H or C 12 --H; 5.4 (s 1H) C 17 --H; 3.8 (s 3H), 3.6 (s 3H), 3.5 (s 3H) C 16 --COOCH 3 , C 16' --COOCH 3 and C 11 --OCH 3 ; 2.7 (s 3H) N a --CH 3 ; 2.1 (s 3H) C 17 --OCOCH 3 ; 0.8-0.4 (2 t, 6H) C 18 --H and C 18' --H.
  • Mass spectrum M + ⁇ at m/e: 792, 763, 733, 631, 539, 469, 394, 379, 282, 135, 122, 121.
  • Mass spectrum M + ⁇ at m/e 718, 687, 659, 536, 395, 336 (100%), 295, 293, 135, 122.
  • the present invention also relates to medicinal compounds containing at least one new bis-indolic compound or one of its salts, in association with any other pharmaceutically compatitible produce, which may be inert or physiologically active.
  • compositions may be present in any form which is appropriate to the method of administration foreseen.
  • the parenteral method is the preferred method of administration, in particular the intravenous method.
  • composition according to the invention for parenteral administration may be aqueous or non-aqueous sterile solutions, suspension or emulsions.
  • a solvent or vehicle it is possible to use propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, in particular ethyl oleate.
  • These compositions may also contain adjuvants in particular wetting, emulsifying and dispersing agents.
  • Sterilisation can be carried out in several ways, for example using a bacteralogical filter, by incorporating sterilising agents into the composition, by irradiation or heating. They may also be prepared in the form of sterile solid compositions which can be dissolved or dispersed at the time of use in sterile water or any other injectable sterile medium.
  • the new bis-indolic compounds or their salts are active in the treatment of cancer, namely solid tumors or leukemia in daily doses of between 10 and 20 mg per day for an adult.
  • a solution is prepared containing 10 mg/cm 3 of active material by dissolving 1 g of the product I-1 of Example 1 in 100 cm 3 of apyrogenic physiological solution.
  • the solution obtained is distributed aseptically into 2 cm 3 ampoules with 1 cm 3 per ampoule.
  • the ampoules are sealed and each contain 10 mg of active principle.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Indole Compounds (AREA)
US06/275,050 1974-12-30 1981-06-18 Bis-indolic compounds Expired - Lifetime US4769453A (en)

Applications Claiming Priority (2)

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FR7443221 1974-12-30
FR7443221A FR2296418B1 (enrdf_load_stackoverflow) 1974-12-30 1974-12-30

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US (2) US4769453A (enrdf_load_stackoverflow)
JP (1) JPS6056719B2 (enrdf_load_stackoverflow)
BE (1) BE837073A (enrdf_load_stackoverflow)
CA (1) CA1132544A (enrdf_load_stackoverflow)
CH (1) CH606023A5 (enrdf_load_stackoverflow)
DE (1) DE2558124A1 (enrdf_load_stackoverflow)
FR (1) FR2296418B1 (enrdf_load_stackoverflow)
GB (1) GB1536407A (enrdf_load_stackoverflow)
HU (1) HU177154B (enrdf_load_stackoverflow)
NL (1) NL184418C (enrdf_load_stackoverflow)

Cited By (8)

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Publication number Priority date Publication date Assignee Title
WO1997005869A1 (en) * 1995-08-08 1997-02-20 Albany Medical College Ibogamine congeners
US5620985A (en) * 1993-07-21 1997-04-15 Pierre Fabre Medicament Antimitotic binary alkaloid derivatives from catharanthus roseus
US20050137169A1 (en) * 2003-12-04 2005-06-23 Scott Ian L. Vinca derivatives
US20050176748A1 (en) * 2003-12-04 2005-08-11 Scott Ian L. Vinorelbine derivatives
US20080119502A1 (en) * 2006-09-12 2008-05-22 Amr Technology, Inc. Vinca derivatives
US20080125451A1 (en) * 2006-09-12 2008-05-29 Amr Technology, Inc. Vinorelbine derivatives
US9399642B2 (en) 2012-01-10 2016-07-26 William Allen Boulanger Pharmaceutical intermediates and methods for preparing the same
US12116372B1 (en) 2023-12-14 2024-10-15 William Allen Boulanger Process for preparing methyl 3-bromo-2-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)propanoate

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US4841045A (en) * 1985-03-12 1989-06-20 University Of Vermont & State Agricultural College Synthesis of vinblastine and vincristine type compounds
JPS62502684A (ja) * 1985-03-12 1987-10-15 ザ・ユニバ−シテイ・オブ・バ−モント・アンド・ステイト・アグリカルチユラル・カレツジ ビンブラスチン及びビンクリスチン型化合物の合成
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US5047528A (en) * 1987-01-22 1991-09-10 University Of Bristish Columbia Process of synthesis of vinblastine and vincristine
AU1066888A (en) * 1987-01-22 1988-08-04 University Of British Columbia, The Process for the synthesis of vinblastine and vincristine
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FR2779146B1 (fr) 1998-06-02 2002-01-18 Roowin Nouveaux derives de vinca-alcaloides et procedes de preparation
EP2266607A3 (en) 1999-10-01 2011-04-20 Immunogen, Inc. Immunoconjugates for treating cancer
US9394294B2 (en) 2010-05-11 2016-07-19 Demerx, Inc. Methods and compositions for preparing and purifying noribogaine
US8765737B1 (en) 2010-05-11 2014-07-01 Demerx, Inc. Methods and compositions for preparing and purifying noribogaine
US8637648B1 (en) 2010-06-22 2014-01-28 Demerx, Inc. Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier
US8802832B2 (en) 2010-06-22 2014-08-12 Demerx, Inc. Compositions comprising noribogaine and an excipient to facilitate transport across the blood brain barrier
US9358237B2 (en) 2010-07-23 2016-06-07 Demerx, Inc. Noribogaine compositions
EP2481740B1 (en) 2011-01-26 2015-11-04 DemeRx, Inc. Methods and compositions for preparing noribogaine from voacangine
US8742096B2 (en) 2011-03-28 2014-06-03 Demerx, Inc. Methods and compositions for preparing noribogaine from voacangine
US9617274B1 (en) 2011-08-26 2017-04-11 Demerx, Inc. Synthetic noribogaine
JP2015500833A (ja) 2011-12-09 2015-01-08 デメレックス， インコーポレイテッド ノルイボガインのリン酸エステル
US8877921B2 (en) 2012-01-25 2014-11-04 Demerx, Inc. Synthetic voacangine
EP2934541A4 (en) 2012-12-20 2016-08-03 Demerx Inc NORIBOGAINE SUBSTITUTE
US8940728B2 (en) 2012-12-20 2015-01-27 Demerx, Inc. Substituted noribogaine
US9045481B2 (en) 2012-12-20 2015-06-02 Demerx, Inc. Substituted noribogaine

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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5620985A (en) * 1993-07-21 1997-04-15 Pierre Fabre Medicament Antimitotic binary alkaloid derivatives from catharanthus roseus
WO1997005869A1 (en) * 1995-08-08 1997-02-20 Albany Medical College Ibogamine congeners
US6211360B1 (en) 1995-08-08 2001-04-03 Albany Medical College Ibogamine congeners
US20080108644A1 (en) * 2003-12-04 2008-05-08 Amr Technology, Inc. Vinca derivatives
US8053428B2 (en) 2003-12-04 2011-11-08 Albany Molecular Research, Inc. Vinorelbine derivatives
WO2005055939A3 (en) * 2003-12-04 2005-12-29 Amr Technology Inc Vinca derivatives
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US9399643B2 (en) 2012-01-10 2016-07-26 William Allen Boulanger Pharmaceutical intermediates and methods for preparing the same
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CH606023A5 (enrdf_load_stackoverflow) 1978-10-13
GB1536407A (en) 1978-12-20
NL184418B (nl) 1989-02-16
FR2296418A1 (enrdf_load_stackoverflow) 1976-07-30
BE837073A (fr) 1976-06-24
NL7515193A (nl) 1976-07-02
HU177154B (en) 1981-08-28
DE2558124C2 (enrdf_load_stackoverflow) 1991-04-18
DE2558124A1 (de) 1976-07-01
CA1132544A (en) 1982-09-28
JPS5188999A (en) 1976-08-04
FR2296418B1 (enrdf_load_stackoverflow) 1978-07-21
NL184418C (nl) 1989-07-17
US4737586A (en) 1988-04-12
JPS6056719B2 (ja) 1985-12-11

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